Reactome | Retromer associates with WLS

Retromer associates with WLS

Stable Identifier

R-HSA-3247839

Type

Reaction [binding]

Species

Homo sapiens

Compartment

early endosome membrane, cytosol

ReviewStatus

5/5

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Retromer is a conserved multi-protein complex that is required for retrograde transport of transmembrane proteins. It was initially characterized in yeast as a pentameric complex required for the recycling of the transmembrane receptor VPS10 to the trans-Golgi, and was subsequently shown to be conserved in flies, worms and humans. In humans, retromer consists of a cargo-recognition subcomplex made up of VPS35, VPS26 and VPS29 and a membrane-targeting subcomplex containing a heterodimer of SNX proteins (SNX1 or 2 paired with SNX5 or 6). The SNX proteins contain a BAR domain that is believed to promote membrane curvature, and SNX-BAR proteins are thought to aid in the formation of endosomal membrane tubules into which cargo is loaded (reviewed in Pfeffer, 2001; Seaman, 2012).

Retromer is required for the recycling of WLS to the Golgi to allow further rounds of WNT-ligand delivery to the plasma membrane (Coudreuse et al 2006; Belenkaya et al 2008; Port et al, 2008). In the absence of essential retromer component VPS35 or VPS26, WLS is diverted to the MVB and degraded, and WNT ligand accumulates inside the cell; overexpression of WLS is sufficient to rescue the vps35 defect in WNT signaling (Belenkaya et al, 2006; Franch-Marro et al, 2008). WLS and retromer colocalize on endosomal structures and WLS and VPS35 co-precipitate in pull down studies (Belenkaya et al, 2006; Port et al, 2008; Franch-Marro et al, 2008).

Several recent studies have suggested that WLS recycling depends on a WNT-specific retromer in which the SNX-BAR proteins of the classic complex are replaced by SNX3 (Zhang et al, 2011; Harterink et al, 2011; reviewed in Johannes and Wunder, 2011). Unlike SNX1/2/5/6, SNX3 does not contain a BAR domain, and WLS is suggested to accumulate in endocytic vesicles rather than in the tubular structures of the 'classic' retromer (Harterink et al, 2011; Zhang et al, 2011). SNX3 is recruited from the cytosol to the early endosome through the interaction of its PX domain with PIP3 in the membrane. Mutation of critical residues in the PX domain abolish the interaction with PIP3 and ablate endsomal recruitment of SNX3 (Xu et al, 2001; Zhang at al, 2011; Harterink et al, 2011). SNX3 has been shown to co-immunoprecipitate with VPS35 and VPS26, and some studies have also shown a direct interaction between SNX3 and WLS (Zhang et al, 2011; Harterink et al, 2011).

Literature References

PubMed ID	Title	Journal	Year
18160348	The retromer complex influences Wnt secretion by recycling wntless from endosomes to the trans-Golgi network Belenkaya, TY, Wu, Y, Tang, X, Zhou, B, Cheng, L, Sharma, YV, Yan, D, Selva, EM, Lin, X	Dev. Cell	2008
21725319	A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion Harterink, M, Port, F, Lorenowicz, MJ, McGough, IJ, Silhankova, M, Betist, MC, van Weering, JR, van Heesbeen, RG, Middelkoop, TC, Basler, K, Cullen, PJ, Korswagen, HC	Nat. Cell Biol.	2011
18193032	Wingless secretion promotes and requires retromer-dependent cycling of Wntless Port, F, Kuster, M, Herr, P, Furger, E, Bänziger, C, Hausmann, G, Basler, K	Nat. Cell Biol.	2008
11433298	SNX3 regulates endosomal function through its PX-domain-mediated interaction with PtdIns(3)P Xu, Y, Hortsman, H, Seet, L, Wong, SH, Hong, W	Nat. Cell Biol.	2001
11231171	Membrane transport: retromer to the rescue Pfeffer, SR	Curr. Biol.	2001
22041890	SNX3 controls Wingless/Wnt secretion through regulating retromer-dependent recycling of Wntless Zhang, P, Wu, Y, Belenkaya, TY, Lin, X	Cell Res.	2011
18193037	Wingless secretion requires endosome-to-Golgi retrieval of Wntless/Evi/Sprinter by the retromer complex Franch-Marro, X, Wendler, F, Guidato, S, Griffith, J, Baena-Lopez, A, Itasaki, N, Maurice, MM, Vincent, JP	Nat. Cell Biol.	2008
21725318	The SNXy flavours of endosomal sorting Johannes, L, Wunder, C	Nat. Cell Biol.	2011
16645052	Wnt gradient formation requires retromer function in Wnt-producing cells Coudreuse, DY, Roël, G, Betist, MC, Destrée, O, Korswagen, HC	Science	2006
23148298	The retromer complex - endosomal protein recycling and beyond Seaman, MN	J. Cell. Sci.	2012